Copper-Catalyzed Tandem Conjugate Addition-Electrophilic Trapping: Ketones, Esters, and Nitriles as Terminal Electrophiles

Article abstract of DOI:10.1021/ja030603l

Exposure of enone substrates 1a?18a, which possess appendant ketone, ester, and nitrile moieties, to Et₂Zn in the presence of catalytic Cu(OTf)₂/P(OEt)₃ provides the cyclized products in good to excellent yields and diastereoselectivities. These results represent the first use of ketones, esters, and nitriles as terminal electrophiles in Cu-catalyzed conjugate addition?electrophilic trapping. Copyright

Full text of DOI:10.1021/ja030603l

Published on Web 03/18/2004
Copper-Catalyzed Tandem Conjugate Addition-Electrophilic Trapping:
Ketones, Esters, and Nitriles as Terminal Electrophiles
Kyriacos Agapiou, David F. Cauble, and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received October 29, 2003; E-mail: mkrische@mail.utexas.edu
Table 1. Cu-Catalyzed Tandem Conjugate Addition-Aldol
Tandem C-C bond formations are attractive methodological
targets, as they enable rapid increases in molecular complexity.1,2
Recently, we have explored conjugate addition-electrophilic trap-
ping as a modular platform for catalytic reaction development.3-7
Through variation of the nucleophilic initiator and electrophilic trap,
a variety of catalytic conjugate addition-cyclizations are enabled:
Co- and Rh-catalyzed conjugate reduction-aldol cyclizations,3,4
related Co- and phosphine-catalyzed Michael cyclizations,3,5 a two-
component catalyst system for enone cycloallylation,6 and finally,
a diastereo- and enantioselective Rh-catalyzed conjugate addition-
aldol cyclization have been developed.7 To extend the latter reaction
type, a study of Cu-catalyzed conjugate addition-electrophilic
trapping was undertaken. Here, we report that exposure of enone
substrates 1a-18a, which possess appendant ketone, ester, and
nitrile moieties, to organozinc reagents in the presence of catalytic
Cu(OTf)2/P(OEt)3 provides the cyclized products in good to
excellent yields and diastereoselectivities. These results represent
the first use of ketones, esters and nitriles as terminal electrophiles
in Cu-catalyzed conjugate addition-electrophilic trapping.
Cyclizationa
Cu-catalyzed addition of organozinc reagents to R,â-unsaturated
carbonyl compounds has been the subject of intensive investigation.8
Enantioselective variants of the parent transformation now encom-
pass diverse R,â-unsaturated substrates.9 Moreover, trapping of the
intermediate Zn-enolates has been achieved using aldehydes,10 Pd-
π-allyls,10a,11 halides and tosylates,12 and oxocarbenium ions13 (by
way of acetal decomposition). While ketone aldols are observed
as homocondensation side products in Cu-catalyzed conjugate
addition,10d the deliberate use of ketones as electrophilic traps is
reported to fail in the absence of strong Lewis acidic additives.13
To our knowledge, the use of esters and nitriles as terminal
electrophiles in Cu-catalyzed conjugate addition remains unex-
plored.
It was recognized that the limitations inherent to the use of such
recalcitrant electrophiles Vis-a`-Vis intermolecular condensation
might be overcome in the case of the analogous intramolecular
processes, because of a reduced entropy of activation. To assess
the veracity of this analysis, keto-enone 2a was subjected to
conditions for Cu-catalyzed conjugate addition.
a See Supporting Information for detailed experimental procedures. b The
structural assignment of 6b, 8b-10b is based on X-ray diffraction analysis.
c Compound 1d was prepared via Cu-catalyzed addition of the Grignard
reagent as described in the Supporting Information. d Reflects ratio of syn-
aldol to anti-aldol product. e Reflects ratio of cis-fused to trans-fused
hydrindane.
Gratifyingly, it was found that exposure of keto-enone 2a to
Et2Zn in the presence of Cu(OTf)2 and triethyl phosphite gave the
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10.1021/ja030603l CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cu-Catalyzed Tandem Conjugate Addition-Dieckmann
and Blaise Condensationa
philic trapping has been demonstrated. Future studies will focus
on the development of related catalytic tandem C-C bond forming
transformations with attendant applications toward the total syn-
thesis of complex natural products.
Acknowledgment. Acknowledgment is made to the Research
Corporation Cottrell Scholar Award (CS0927), the Alfred P. Sloan
Foundation, the Camille and Henry Dreyfus Foundation, Eli Lilly,
and the UT Austin Center for Materials Research (CMC) for partial
support of this research.
Supporting Information Available: Spectral data for all new
compounds (1H NMR, 13C NMR, IR, HRMS) (CIF and PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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desired cyclization product 2b in nearly quantitative yield and as a
single diastereomer. Under these optimized conditions, Cu-catalyzed
tandem conjugate addition-aldolization of keto-enone substrates
1a-10a was demonstrated (Table 1). Inspired by these results and
the established ability of zinc-enolates to condense with recalcitrant
electrophiles such as nitriles,14 related catalytic tandem conjugate
addition-Dieckmann and Blaise cyclizations were explored. Upon
application of standard reaction conditions to mono-enone mono-
esters 11a-14a and mono-enone mono-nitriles 15a-18a, the
corresponding cyclized products were obtained in excellent yield
(Table 2). Finally, to demonstrate the feasibility of developing
enantioselective variants of these tandem C-C bond formations,
enone-dione 6a was subjected to standard reaction conditions using
Feringa’s phosphoramidite ligand.8c While diastereoselectivity
suffered, high levels of asymmetric induction were observed.
In summation, the use of ketones, esters, and nitriles as terminal
electrophiles in Cu-catalyzed tandem conjugate addition-electro-
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